Dyspepsia (acid dyspepsia) is a common disorder. Heartburn is a symptom of dyspepsia. It is estimated that 44% of Americans have heartburn at least once monthly but that only about 25% of them are seeing the doctor because of their dyspepsia problem. Symptoms associated with dyspepsia are for instance upper abdominal pain/discomfort and heartburn, indigestion, “sour” stomach, and gastro-esophageal reflux.
Dyspepsia is a multi-factorial disease and may be associated with organic pathology such as duodenal ulcer, gastric ulcer, esophagitis, Barrett's esophagus or gastro-duodenal inflammation (e.g., Helicobacter pylori infection). Dyspepsia also includes conditions where no organic pathology can be found, e.g., non-ulcer dyspepsia (NUD) or functional dyspepsia.
Dyspepsia can be controlled by administration of medicines that reduce the pH in the stomach. Therapeutic agents effective in the treatment of dyspepsia include gastric acid suppressing agents, such as histamine H2 receptor antagonists (in the following called H2 receptor antagonists), acid susceptible proton pump inhibitors, antacids/alginates, anticholinergics and prokinetic agents. They can be distinguished by their mechanism of action, safety profile, and pharmacokinetics. The stomach pathogen Helicobacter pylori has been associated with dyspepsia, gastro-duodenal ulcer disease and stomach cancer. The treatment of H. pylori infection usually comprises the administration of a combination of acid secretion suppressing agents and one or two antibiotic agents.
The therapeutic effect on dyspepsia related discomfort and organic lesions when inhibiting acid production by administration of acid secretion-inhibiting drugs is related to the degree of acid inhibition as well as to the onset and duration of action of the particular drug. The majority of patients who have symptomatic acid reflux disease have a normal esophageal mucosa or only a mild degree of esophagitis. Treatment to relieve symptoms as they occur may be the best way to manage these patients, to whom the speed of symptom relief is of primary importance.
Antacid agents, that is, acid neutralizing agents, and alginates are the first therapeutic choice in the treatment of mild heartburn. They have a extremely short duration of action but are seen as inexpensive and safe. Antacid agents work locally through a neutralization of gastric acid. Alginates provide some mechanical protection against reflux of gastric acid into the esophagus. The main advantages of antacid agents and alginates are, that they provide fast relief of symptoms. The main disadvantage of antacid agents and alginates is the extremely short duration of action and dosing has to be repeated frequently to keep the patients free of symptoms, further that antacids often do not provide symptom resolution, i.e. complete relief of symptoms.
Several classes of compounds are known which affect the secretion of gastric acid. Among them proton pump inhibitors, such as the substituted benzimidazoles omeprazole, lansoprazole, rabeprazole, pantoprazole, and H2 receptor antagonists, such as cimetidine, ranitidine, famotidine, are the most prominent ones. H2 receptor antagonists and acid susceptible proton pump inhibitors are widely prescribed for reducing gastric acid secretion systemically. After 5 days' treatment, acid susceptible proton pump inhibitors have in clinical studies been proven to be very effective in providing symptom resolution in patients with dyspepsia associated with gastric ulcers, duodenal ulcers, reflux esophagitis and gastro-esophageal reflux without esophagitis. Acid susceptible proton pump inhibitors and H2 receptor antagonists, respectively, have also proven to be effective in curing H. pylori infection in combination with one or two antibiotics (Gschwandtler M et al., Aliment Pharmacol Ther 1999, 13(8):1063-9). It is established that omeprazole is superior to H2 receptor antagonists regarding healing of gastro-duodenal and esophageal lesions as well as providing dyspeptic symptom resolution in these conditions (Eriksson S., European Journal of Gastroenterology & Hepatology 1995, 7:465).
Various combinations of antacid and/or mucosa protecting agents with agents that reduce acid secretion have been disclosed to be useful in treating dyspepsia.
WO 95/017080 describes a composition for use in the treatment of for instance heartburn comprising an H2 receptor antagonist, such as famotidine, and an alginate and optionally simethicone (an activated polysiloxane).
EP 338861 A describes a solid pharmaceutical preparation consisting of an antacid and excipients which is proposed to be used in combination with an acid susceptible proton pump inhibitor or any other substance inhibiting gastric acid secretion. There is no suggestion to combine these substances in a fixed unit dosage form.
U.S. Pat. No. 5,244,670 A describes an ingestible pharmaceutical composition comprising a substance selected from the group consisting of antacid agents, acid secretion prevention agents, bismuth-containing agents and their mixtures, and 3-(1-menthoxy)-propane-1,2-diol which is present to provide a cooling sensation to the throat.
WO 97/25066 discloses a pharmaceutical formulation comprising a combination of an acid susceptible proton pump inhibitor or an H2 receptor antagonist and one or more antacid agents or alginates.
Neither acid susceptible proton pump inhibitors nor H2 receptor antagonists, alone or in combination with antacids and/or alginates, provide fully satisfactory quick and lasting relief to patients, to whom the speed of symptom relief is of primary importance but who also desire to be free of symptoms for a longer period of time.